Echocardiography and the B-type natriuretic peptides (BNPs) provide powerful incremental assessment of cardiac function, clinical status, and outcome across the spectrum of cardiac disease. There is strong evidence to support their integrated use in the diagnosis and management of cardiovascular disease. Amino-terminal pro-BNP (NT-proBNP) or BNP may guide more effective screening for asymptomatic left ventricular dysfunction; Doppler echocardiography improves the accuracy of heart failure diagnosis in the setting of intermediate BNP or NT-proBNP levels. Combined assessment of peptides and echocardiography provides more powerful stratification of risk across all stages of heart failure, and integrated use of both tests may guide decision-making for timely intervention in valvular heart disease.

Abstract

Echocardiography and the B-type natriuretic peptides (BNPs) provide powerful incremental assessment of cardiac function, clinical status, and outcome across the spectrum of cardiac disease. There is strong evidence to support their integrated use in the diagnosis and management of cardiovascular disease. Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) or BNP may guide more effective use of echocardiography in screening for asymptomatic left ventricular dysfunction; Doppler echocardiography improves the accuracy of heart failure diagnosis in the setting of intermediate BNP or NT-proBNP levels. Combined assessment of peptides and echocardiography provides more powerful stratification of risk across all stages of heart failure, and integrated use of both tests may identify subjects with valvular disease at greatest risk for progression and guide decision-making for timely intervention.

Since their discovery and characterization, B-type natriuretic peptides have become firmly established as biomarkers for heart failure diagnosis and for prognosis across the spectrum of cardiovascular disease (1–3). The relationship between the B-type peptides and echocardiographic measures of cardiac structure and function has been widely explored. Peptide measurements provide information complementary or incremental to echocardiography for assessment of cardiac function, clinical status, and outcome. We review these data and consider the potential clinical applications of echocardiography integrated with B-type natriuretic peptide testing.

The BNP gene encodes pre-pro-BNP, a 134-amino acid (aa) molecule from which BNP signal peptide is cleaved to produce proBNP (amino acids 1 to 108) (4). ProBNP and its two cleavage products, the inactive amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (aa 1 to 76) and the bioactive molecule BNP (aa 77 to 108) (Fig. 1) are all present in the circulation. Although secretion of BNP and NT-proBNP is equimolar, BNP is actively cleared through natriuretic peptide C-receptors and by neutral endopeptidase, resulting in significantly lower plasma levels and a shorter half-life (21 min) than NT-proBNP (70 min), for which clearance mechanisms beyond renal filtering are less certain. Further processing of proBNP, NT-proBNP, and BNP within the circulation produces truncated forms presumably variably recognized by immunoassays and possessing variable bioactivity (5). This appears to have little impact on clinical application of current well-validated immunoassays for BNP and NT-proBNP (5).

Pro-B-type natriuretic peptide (proBNP) is synthesized primarily within cardiomyocytes and is largely cleaved to form bioactive BNP and the inert marker molecule amino-terminal proBNP (NT-proBNP), the major circulating forms. Further processing within the circulation produces truncated forms of all 3 peptides that can be identified in plasma. Modified with permission from Lam et al (5).

BNP is not stored but is synthesized and secreted constitutively in response to cardiomyocyte stretch (4). Increased ventricular or atrial wall stress, reflecting volume or pressure overload, is the primary driver of myocyte stretch-mediated secretion, but ischemia, neurohormones, and cytokines also stimulate or modify BNP gene expression (4).

Plasma levels of B-type natriuretic peptides

Validated commercial assays are available for BNP and NT-proBNP (6). Each assay has different performance characteristics and recognizes different epitopes on the BNP or NT-proBNP molecule. Although there is generally strong correlation between assays, absolute peptide values may vary considerably, so clinicians should know the reference range and performance characteristics of their local assay (6,7).

Plasma levels of BNP and NT-proBNP increase with age and are lower in men than in women (8). Levels are inversely related to body mass index and lean mass (9) and increase with worsening glomerular filtration rate (10). Even in stable subjects, peptide levels vary with repeat testing as a consequence of assay characteristics and biological variation (11). Relative variation is greater in normal subjects, in whom absolute levels are low. In disease states, absolute levels are higher and relative variation is lower. In stable heart failure subjects, changes of more than 23% for NT-proBNP or 43% for BNP are likely to indicate a change beyond that due to background biological variation (11).

BNP and Echocardiographic Indexes of Cardiac Function

Given synthesis primarily by cardiomyocytes, it is not surprising that the greatest secretion of B-type peptides is from the left ventricle (LV). BNP and NT-proBNP levels correlate positively with LV dimensions, volumes, and mass in a variety of settings and populations and are inversely related to LV ejection fraction (LVEF) (3,12–15). Peptide levels are higher with left ventricular hypertrophy (LVH) (14) and are higher still in subjects with LVH and clinical heart failure.(16)

BNP and NT-proBNP levels also reflect left atrial size, correlating positively with left atrial volume, particularly in the general population and in patients with heart failure with preserved systolic function (13,20,21). In acutely decompensated heart failure or in subjects with advanced systolic heart failure, the relationship between left atrial volume and BNP appears diminished, possibly reflecting proportionately greater peptide secretion from the left and right ventricles in this context.

Right ventricle

The right ventricle (RV) contributes to plasma levels of BNP or NT-proBNP, with either normal or impaired LVEF. Levels of both peptides correlate with measures of RV size and function, increasing with greater dilatation and systolic dysfunction, and with increasing RV pressure estimates (18,22).

Detection of Elevated Left Ventricular Filling Pressures

Plasma levels of the B-type peptides reflect measurements of LV filling pressure, but the relationship is often modest and dependent on clinical context (23). In patients undergoing routine coronary angiography (24), BNP and/or NT-proBNP correlate strongly with LV end diastolic pressure (LVEDP) and exhibit modest accuracy for detection of raised LVEDP (23,24). Smaller studies in subjects with stable systolic dysfunction demonstrate similar strong correlations between BNP or NT-proBNP and either LVEDP or pulmonary capillary wedge pressure (PCWP) (25,26). In this context, peptide levels are elevated and exhibit good specificity but reduced sensitivity and overall accuracy for detection of elevated filling pressures (25). When LV ejection fraction is preserved but diastolic function is impaired, the correlation between BNP or NT-proBNP and invasively measured filling pressures is weaker (r = ∼0.45), but negative predictive values (∼90%) for elevated LVEDP remain high (19). In acute decompensated heart failure (ADHF), where background BNP or NT-proBNP levels are significantly elevated, the correlation between peptide levels and filling pressure is weaker, especially in advanced heart failure or unselected intensive care patients (23,27). Changes in peptide levels during therapy for ADHF reflect clinical and hemodynamic changes, but peak peptide changes lag behind the latter (27,28).

The modest relationship between NT-proBNP or BNP and LV filling pressures is consistent with the complexity of factors influencing secretion and clearance. In addition to the effects of age, sex, renal function, and neurohormonal/cytokine status, secretion from the RV and the left atrium contribute to absolute peptide levels. Left ventricular geometry is also important, with dilated ventricles secreting more peptide for a given filling pressure due to greater wall stress and chamber mass (15,18).

A single value for BNP or NT-proBNP is therefore unlikely to provide reliable estimation of filling pressures across individuals, although very low levels retain strong negative predictive values for an elevated filling pressure in most settings (23). Within individuals, however, changes in BNP may reflect changes in filling pressure, as has been demonstrated in subjects with implantable monitoring devices, where serial BNP measurements correlate significantly with ambulatory device-based estimates of filling pressure (29).

In contrast, accurate estimation of LV filling pressures by Doppler echocardiography has been widely validated. Transmitral and pulmonary venous filling indexes and more particularly, the E/Ea ratio, are now established as markers of filling pressure that have been widely adopted across a broad range of clinical settings (30–32). There have been few comparative studies of echocardiography with BNP, however Dokainish et al. (27) compared validated Doppler echocardiographic indexes with BNP for detection of PCWP >15mm Hg in patients admitted to the intensive care unit. In subjects with established cardiac disease, a BNP level >400 pg/ml demonstrated similar sensitivity (91%) but poorer specificity (51% vs. 91%) and overall accuracy than Doppler indexes such as E/Ea for detection of a PCWP >15 mm Hg. However, in subjects without cardiac disease, BNP proved more sensitive (81% vs. 74%) and specific (83% vs. 72%) than Doppler indexes (27). These findings indicate that in subjects with known cardiac disease, Doppler echocardiography provides superior estimation of elevated filling pressures. Where there is no history of cardiac disease, peptide measurement may be a preferred initial strategy for detecting elevated filling pressure.

Detection of Left Ventricular Systolic and Diastolic Dysfunction

The accuracy of BNP or NT-proBNP in screening for LV structural and functional abnormalities has been tested in community, hospital, and high-risk populations and appears to depend on the abnormality in question and its prevalence within that population (3,13,20,33–35).

In selected subjects referred for echocardiography, BNP has good sensitivity and specificity for detecting systolic (LVEF <40% to 50%) or diastolic dysfunction. Low peptide levels have high negative predictive value; specificity and positive predictive values increase when the prevalence of LV dysfunction is higher (17,36). Maisel et al. (36) demonstrated that a BNP level of ≥75 pg/ml had an overall accuracy of 90% for detecting either systolic (LVEF <50%) or diastolic dysfunction (impaired relaxation pattern or worse on transmitral filling). BNP levels did not differentiate systolic from primary diastolic dysfunction with preserved LVEF. Lubien et al. (17) assessed 294 patients with normal systolic function (LVEF >50%) referred for echocardiography. BNP levels rose with increasing diastolic dysfunction and were higher still if clinical heart failure was present (Fig. 3). A BNP level of 65 pg/ml detected any diastolic dysfunction in this context with a sensitivity of 85%, specificity of 83%, and overall accuracy of 84%. Accuracy was greater when only restrictive filling was considered (17).

Community screening

In community settings, up to one-half of all patients with LV dysfunction may be clinically undetected (37). Several studies have assessed screening of the general population with BNP or NT-proBNP to detect systolic dysfunction (LVEF <50%), increased LV mass, or diastolic dysfunction graded on the basis of transmitral filling as moderate (pseudonormal) or severe (restrictive) (33–35,38,39). The prevalence of LV dysfunction in each study was low (≤6%), but these studies consistently demonstrate a high negative predictive value (93% to 99%) when BNP or NT-proBNP levels are low; values for specificity and overall accuracy are lower (33,35). The lesser accuracy of detection of asymptomatic LV dysfunction by NT-proBNP and BNP in the community setting may reflect confounding from noncardiac influences, including age, sex, and renal function, in the setting of generally low peptide levels and a low prevalence of LV dysfunction. The effect of body mass on peptide levels may add to background noise that reduces the utility of peptide screening, unlike in heart failure diagnosis, in which the accuracy of threshold peptide cut-points appears less affected by body mass (3,9). The Framingham study group found that use of a single sex-adjusted BNP level did not significantly improve detection of LV systolic dysfunction (diastolic function was not considered) or LVH over standard clinical and electrocardiographic parameters (35). In subjects from Olmsted County, although very low levels of BNP excluded significant LV dysfunction, unadjusted levels appeared suboptimal for routine screening of the general population, with confirmatory echocardiography necessary in up to 40% of the study population and up to 60% of cases missed when a single unadjusted BNP cut-point value was applied (33). The same group compared NT-proBNP to BNP in 1,869 community subjects and found that use of age- and sex-adjusted cut-point factors improved accuracy, with sensitivity and specificity between 90% and 100% for NT-proBNP in detecting LVEF <40% (13). Both NT-proBNP and BNP were less robust when screening for diastolic dysfunction, alone or in combination with systolic dysfunction.

Although portable echocardiography may provide a more cost-effective approach to screening for LV dysfunction (40,41), integrated use of NT-proBNP using age- and sex-adjusted cut-points could provide helpful screening for systolic dysfunction, but not for isolated diastolic dysfunction (20,42). Importantly, BNP and NT-proBNP may function best in combination with other tests. Combining BNP with electrocardiogram or clinical features increases the positive predictive value and overall accuracy for detection of LV dysfunction (43). Several studies indicate that screening with BNP or NT-proBNP in combination with clinical parameters is cost-effective in reducing the number of formal echocardiographic studies needed to identify LV dysfunction (44). BNP and NT-proBNP may function better as a marker of “cardio-renal dysfunction” rather than specifically for LV dysfunction (20). In this context, peptide values below the 97.5th percentile for the normal population, have high negative predictive value, essentially ruling out cardio-renal abnormalities in asymptomatic subjects (45).

Diagnosis of Heart Failure

The prompt and accurate diagnosis of heart failure facilitates decision making and management in primary care and in the emergency room (3,46,47). However, early diagnosis remains a significant challenge in these settings, with initial diagnoses based on clinical assessment often being incorrect (46,47). BNP or NT-proBNP levels are elevated in patients with ADHF, and multiple studies have demonstrated the value of BNP or NT-proBNP for diagnosis of acute heart failure, regardless of LVEF (46,48,49). In an acutely dyspneic patient, low peptide levels (<100 pg/ml for BNP [49], <300 pg/ml for NT-proBNP [48]) rule out ADHF with a negative predictive value of >95%; very high peptide levels can achieve positive predictive values ≥85% for ADHF (48). In many of these studies, echocardiography was included in the gold standard assessment of ADHF diagnosis. Smaller studies comparing echocardiography with peptide methods show that BNP has similar accuracy to any single echocardiographic index (such as E/Ea) for diagnosis of heart failure; comprehensive Doppler echocardiography provides improved specificity (50–52). Comprehensive echocardiography provides a particular advantage when BNP or NT-proBNP levels fall in the intermediate or “grey” zone. For example, a restrictive transmitral Doppler pattern accurately differentiates acute heart failure from noncardiac causes of acute dyspnea when BNP levels fall between ∼100 and ∼500 pg/ml (Fig. 4) (50,51). Integrated use of peptide measurement followed by targeted Doppler echocardiography could therefore improve the accuracy of early heart failure diagnosis for up to 30% of acutely dyspneic patients who have intermediate peptide levels at presentation (Fig, 5).

Integrated Use of BNP and Echocardiography for Heart Failure Diagnosis

Algorithm for integrated use of B-type natriuretic peptide (BNP) levels and echocardiography for diagnosis of acute heart failure. *Use of age stratified values for amino-terminal pro-B-type natriuretic peptide (NT-proBNP) provides more accurate test performance: <50 years use NT-proBNP >450 pg/ml; 50 to 75 years use NT-proBNP >900 pg/ml; >75 years use NT-proBNP >1,800 pg/ml (48).

BNP or NT-proBNP levels are higher in heart failure with impaired LV systolic function than when LVEF is preserved, consistent with greater wall stress in the former (15,49). However, peptide levels have limited accuracy in differentiating these two entities and cannot replace echocardiography (49).

Monitoring of Heart Failure

Notwithstanding the biological variation seen with repeat peptide measurements, there is growing evidence that serial measurements of BNP or NT-proBNP may be useful for monitoring clinical status and guiding therapy in heart failure (53,54). The greatest benefits are seen in younger patients with systolic heart failure, in whom reductions in mortality and heart failure events have been demonstrated with peptide-guided therapy (53–55).

In contrast, the role of serial imaging in heart failure remains unclear and is generally not advocated in stable patients (41). Repeat measurement of 2-dimensional and Doppler indexes may be limited by reproducibility and measurement variability (41). To date, the value of repeat echocardiographic imaging has not been tested in a randomized study, and the few studies comparing serial echocardiographic imaging and peptide measurement suggest the latter may provide more clinically useful information (56,57). Further studies are needed in this area, particularly to assess integrated use of imaging and peptide monitoring. The concept that threshold changes in peptides levels could guide more optimal use of serial or repeated echocardiographic during follow-up warrants testing.

Echocardiographic indexes of LV systolic and diastolic function are long established prognostic markers in subjects with established cardiovascular disease (58–60). Equally, BNP and NT-proBNP have proven to be among the most powerful independent markers of heart failure events and mortality across the cardiovascular disease spectrum (3).

It is now clear that evaluation of echocardiographic indexes in combination with either BNP or NT-proBNP provides powerful incremental prediction of the risk of new heart failure events or mortality (61–65). This is true for subjects from the general population (61), those with cardiovascular risk factors such as hypertension (65), or after myocardial infarction (64). Integration of BNP levels and Doppler indexes of diastolic function provides powerful incremental prediction in subjects with established heart failure, either at the time of hospitalization (62) or in the community (63). Although abnormalities of either indexes of LV function or of a B-type peptide denote an increased risk of mortality or heart failure, the highest risk is seen in subjects with abnormalities of both LV function and peptide level (Fig. 6) (61–65). Dokainish et al. (62) evaluated 110 subjects hospitalized with heart failure and demonstrated that both BNP levels and E/Ea at discharge were independent predictors of readmission or death. Addition of E/Ea to BNP levels significantly increased the chi-square value of their multivariate model from 17 to 23 and identified nearly all adverse events (47 of 54). These authors suggested that after heart failure hospitalization, an algorithm stratifying patients at discharge by BNP >250 pg/ml and then by E/Ea level >15 could be used to identify most of the subsequent risk of adverse events.

In 268 subjects with dyspnea, the lowest risk for cardiovascular hospitalization or death was seen in subjects with amino-terminal pro-B-type natriuretic peptide (NT-proBNP) <400 pg/ml. In subjects with an elevated NT-proBNP, event rates could be stratified by a ratio of transmitral to mitral annular early diastolic velocity (E/E') above or below 15. Adapted with permission from Whalley et al. (63).

Valvular Heart Disease

Assessment of B-type natriuretic peptide levels in patients with valvular heart disease can provide additional information that may guide decision-making in regard to interventions. Peptide levels rise with increasing severity of aortic stenosis (66,67). Although correlations with transvalvular gradients or indexes of LV function are modest; peptide levels are closely related to symptoms and can assist in their interpretation in this condition. Peptide levels are independent predictors of mortality or heart failure hospitalization in severe aortic stenosis, with BNP levels >100 pg/ml and NT-proBNP levels >600 pg/ml, identifying subjects at higher risk during conservative therapy for moderately severe or severe aortic stenosis (68). Elevated BNP levels also distinguish true from pseudo-stenosis in low gradient aortic stenosis, with levels >550 pg/ml predicting poor survival after aortic valve replacement in this context (66).

Conclusions

Integrated use of echocardiography and plasma B-type natriuretic peptide levels provides powerful incremental assessment of cardiac function, clinical status, and outcome across the spectrum of cardiac disease. NT-proBNP or BNP may guide more effective use of echocardiography in screening for asymptomatic LV dysfunction. Doppler echocardiography improves the accuracy of heart failure diagnosis in the setting of intermediate BNP or NT-proBNP levels. Combined assessment of peptides and echocardiography provides more powerful stratification of risk across all stages of heart failure. Integrated use of both tests may identify subjects with valvular disease at greatest risk for progression and facilitate timely intervention.

Footnotes

Dr. Troughton has received honoraria from Roche Diagnostics as part of their Speaker's Bureau (<$10K). Dr. Richards has received honoraria and research grants from Roche Diagnostics and Advisory Committee fees and grant support from Inverness/Biosite.

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